A large number of cell membrane-anchored growth factors that are synthesized in vivo as a cell membrane-anchored precursor, become soluble in response to cleavage by a processing enzyme (shedding) and express their actions are known.
For example, a heparin-binding EGF-like growth factor (HB-EGF), amphiregulin, epiregulin, transforming growth factor-α (TGF-α) and the like are members of the epidermal growth factor (EGF) family, and it has been clarified that all of the growth factors that belong to the EGF family are biosynthesized as a cell membrane-anchored precursor and become soluble in response to processing. It is known that in general, the solubilized growth factor is then bound to a receptor of the ErbB receptor family in an activated form so as to express the action of a growth factor.
It is known that similarly to these growth factors of the EGF family, tumor necrosis factors (TNF-α) express a large number of physiological actions in an activated form after the cell membrane-anchored precursor has been subjected to processing by proteases.
However, in any case, the role of a fragment that is left in the cell surface (hereinafter, referred to as “remaining fragment”) after the activated form is released by processing has not been known.
On the other hand, the mechanism in which a membrane-anchored receptor releases a signal transducer (second messenger) in response to extracellular stimulations and transduces external signals to a cell is well known. In recent years, a signaling mechanism (regulated intramembrane proteolysis; RIP) has been presented and gained much attention, in which processing of an extracellular domain of a membrane-anchored protein causes a remaining fragment to be translocated into the nucleus, after being subjected to further processing in some cases, and to regulate the transcription of a gene (M. S. Brown et al., Cell, 100, 391-396(2000)).
However, in this as well, only the fact of signaling into the nucleus has been identified, but the meaning of the signal, and the physiological significance such as the subsequent phenomenon caused by the transduced signals have not been clarified yet.
Furthermore, at least regarding HB-EGF, the behavior itself of the remaining fragment after processing has not been known at all
Cell, 100, 391-396 (2000) (M. S. Brown et al.)